The objective of this project is a combined biochemical and genetic analysis of hormonal regulation of plasma membrane phenotype, particularly of those aspects relevant to neoplasia. The glucocorticoid, dexamethasone, induces a program of membrane changes in rat hepatoma cells (HTC) analagous to the cAMP-mediated reversal of transformed phenotype reported in Chinese hamster ovary cells. The well-characterized hormonal responsiveness of HTC cells makes them a suitable experimental model for studying the hormonal regulation of membrane properties. I will investigate the mechanisms by which glucocorticoids and insulin modulate amino acid transport, protease production, intercellular adhesion, cell surface morphology, and the pattern of newly synthesized membrane proteins and secretory proteins in HTC cells; and the ways in which these regulatory programs are related. A major goal of this work is the isolation and characterization of variant cell lines with lesions in specific hormone-inducible functions. We have succeeded in isolating variants selectively resistant to the glucocorticoid inhibition of plasminogen activator activity. These variants should provide a powerful tool for studying both the role of proteases in the regulation of membrane phenotype and the mechanisms by which glucocorticoids regulate protease production. Biochemical and genetic analyses of such variants should improve our understanding of the mechanisms of hormonal regulation of membrane phenotype.